title: Neuron-derived semaphorin 3A is an early inducer of vascular permeability in diabetic retinopathy via neuropilin-1.
abstract: The deterioration of the inner blood-retinal barrier and consequent macular edema is a cardinal manifestation of diabetic retinopathy (DR) and the clinical feature most closely associated with loss of sight. We provide evidence from both human and animal studies for the critical role of the classical neuronal guidance cue, semaphorin 3A, in instigating pathological vascular permeability in diabetic retinas via its cognate receptor neuropilin-1. We reveal that semaphorin 3A is induced in early hyperglycemic phases of diabetes within the neuronal retina and precipitates initial breakdown of endothelial barrier function. We demonstrate, by a series of orthogonal approaches, that neutralization of semaphorin 3A efficiently prevents diabetes-induced retinal vascular leakage in a stage of the disease when vascular endothelial growth factor neutralization is inefficient. These observations were corroborated in Tg(Cre-Esr1)/Nrp1(flox/flox) conditional knockout mice. Our findings identify a therapeutic target for macular edema and provide further evidence for neurovascular crosstalk in the pathogenesis of DR.
authors.affiliation: Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada; Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada.
authors.forename: Agustin
authors.initials: A
authors.lastname: Cerani
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tetreault
authors.forename: Catherine
authors.initials: C
authors.lastname: Menard
authors.forename: Eric
authors.initials: E
authors.lastname: Lapalme
authors.forename: Chintan
authors.initials: C
authors.lastname: Patel
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sitaras
authors.forename: Felix
authors.initials: F
authors.lastname: Beaudoin
authors.forename: Dominique
authors.initials: D
authors.lastname: Leboeuf
authors.forename: Vincent
authors.initials: V
authors.lastname: De Guire
authors.forename: François
authors.initials: F
authors.lastname: Binet
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dejda
authors.forename: Flavio A
authors.initials: FA
authors.lastname: Rezende
authors.forename: Khalil
authors.initials: K
authors.lastname: Miloudi
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D039942:Neuropilin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000503:physiopathology; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1